Metastatic tumors present the most difficult challenge for all therapeutic approaches because of their extensive infiltration and broadcasting of the invasive tumor cells, particularly into the nervous system where they may occupy multiple locations. An eradication of more than 90% of some tumor masses may be accomplished by surgery and subsequent radiotherapy, but relapse invariably follows within months if infiltrating and metastatic cells have not been eliminated.
A number of approaches has been suggested to target and destroy the metastatic cells. One possible method is by cell-mediated vector delivery using retrovirus packaging cells to distribute retroviral vectors on site within brain tumors [Short et al., J. Neurosci. Res. 27, 427-439, 1990; Culver et al., Science 256, 1550-52, 1992; for review, see Kramm et al., Brain Pathol. 5, 345-381, 1995]. However, in most studies these packaging cells are derived from fibroblasts that do not migrate in the brain. In addition to fibroblasts, glioma cells [Tamura et al., Hum Gene Ther 8, 381-9, 1997] and endothelial cells [Lal et al., Proc Natl Acad Sci USA 91, 9695-9, 1994; Ojeifo et al., Cancer Res 55, 2240-44, 1995] have been used as vehicles to migrate throughout a tumor. A major disadvantage of using glioma cell as vehicles is that they themselves are tumorigenic and hence could contribute to the tumor burden. Endothelial cells can migrate within a glioma and are non-tumorigenic, but they have not been observed to move beyond the main tumor mass to target metastatic tumor cells or to “home in” on tumors from a distant source [Ojeifo et al., Cancer Res 55, 2240-44, 1995; Lal et al., Proc Natl Acad Sci USA 91].
The requirement for cells to have high migratory potential within the tumor and toward metastases without tumor formation is ideally fulfilled by neural stem cells (NSCs). NSCs are immature, uncommitted cells that give rise to the array of more specialized cells of the nervous system. They are defined by their ability to self-renew, to differentiate into cells of most (if not all) neuronal and glial lineages, and to populate developing and/or degenerating central nervous system (CNS) regions in multiple anatomical and developmental contexts. Clones of NSCs have been propagated in culture and reimplanted into mammalian brain where they have been shown to reintegrate appropriately and stably express foreign genes. One of the earliest uses of the NSCs as a therapeutic tool was delivering a missing gene product β-glucuronidase throughout the brain of a newborn mouse to correct a model of lysosomal storage disease mucopolysaccharidosis type VII [Snyder et al., Nature, March 1995]. In preliminary studies, NSCs have also been observed to migrate toward damaged brain regions and continue to express exogenous genes [Snyder and Macklis, Clin Neurosci 3, 310-16, 1996].
Most early studies of NSC biology were performed with rodent NSCs, but increasing attention has been focused on human NSCs due to their obvious clinical potential [Black and Loeffler (eds). CANCER OF THE NERVOUS SYSTEM. Blackwell Scientific Inc, Boston, 1996, pp 349-61, Flat et al., Nature Biotech. 11, 1998; Brustle O. et al., Nature Biotech. 11, 1040-49, 1998]. Several human cell lines of neural and stem cells have consequently been isolated from the human fetal telencephalon, propagated in culture, transfected with the lacZ reporter gene and cloned. Human NSCs have been demonstrated to migrate throughout the whole brain, differentiate into neurons and glia, and integrate into the neural architecture and express reporter genes after transplantation into rodent brains [Flat et al., Nature Biotech. 11, 1998].
It would be desirable to have a safe, efficient and convenient system for delivering therapeutic agents to intracerebral tumors, cerebral metastases from an extracerebral tumor, or other extracerebral tumors that metastasize to other organs.